Although the acidic nature of the stratum corneum (SC) has been appreciated for more than a century, both its importance and its origin are poorly understood. Recent studies in adult animals have demonstrated that an acidic SC pH is essential for normal permeability barrier homeostasis and SC integrity and cohesion, and that a neutral SC pH increases the levels of cytokines in the epidermis. An acidic surface pH is achieved in the absence of exogenous mechanisms, such as surface lipids, eccrine gland products, and microbial products, previously thought to be important for SC acidification. Recent studies have shown that three endogenous mechanisms acidify the SC of adult epidermis: 1) free fatty acid generation from phospholipid hydrolysis; 2) a non-energy-dependent, sodium-proton antiporter (NHE1); and 3) urocanic acid generation from histidine. However, studies have shown that the SC of newborn humans has a neutral pH. Over the next several weeks to months the surface pH decreases to adults levels (pH=5.5). As in humans, in a neonatal rat model we have recently shown that the surface pH of newborns is 6.5 to 7.0, and that the surface pH decreases such that by 5-6 days post birth the pH is 5.5 (adult levels). Our studies during the prior funding cycle have shown that activators of PPARa, PPARd, and LXR, stimulate keratinocyte differentiation, permeability barrier homeostasis, and the development of the SC during fetal development. Our preliminary studies have further shown that topical application of ligands of LXR and PPARa accelerates the acidification of the SC in newborn rats. Newborn skin is more susceptible to both external insults and to the development of inflammation than is adult skin. Hypothesis- The SC of newborns has a neutral pH, because one or more of the endogenous mechanisms that are responsible for SC acidification in adults; 1) histidase conversion of histidine to urocanic acid, 2) metabolism of phospholipids to free fatty acids by sPLA2, and/or 3) transport of hydrogen ions into the extracellular space by NHE1, are not yet fully developed in newborn mammal epidermis. With further maturation these pathways develop, and the SC ultimately acidifies, a process that can be accelerated by activation of PPAR alpha, PPAR delta, and LXR. In the neonatal period, this delay in SC acidification results in functional abnormalities, including; a) decreased permeability barrier homeostasis, b) compromised SC integrity and cohesion, and c) increased susceptibility to the development of inflammation with a decreased threshold for the development of persistent inflammatory dermatoses. Objectives- 1) To determine the mechanism(s) that lead to postnatal SC acidification. 2) To determine the adverse consequences of a neutral pH on SC function in the newborn. 3) To determine the mechanisms responsible for the a) abnormalities in permeability barrier homeostasis, b) compromised SC integrity and cohesion, and c) decreased threshold for the development of inflammation in newborn animals with a neutral SC pH. 4) To determine if activators of PPAR alpha, PPAR delta, and/or LXR accelerate the formation of an acidic SC, the mechanism for this acceleration of acidification, and the functional consequences of such an acceleration.